Preparation method and application of impurity of beta 2 adrenal receptor agonist and M receptor antagonist bifunctional active compound
The preparation of impurities of bifunctional active compounds of β2 adrenal receptor agonist and M receptor antagonist through acetylation and hydrogenation reactions has solved the problem of lack of synthesis technology in the prior art, achieved the preparation of high-purity impurities, and met the needs of drug research and development reference products.
Patent Information
- Application Number
- CN202510672929.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-22
- Publication Date
- 2025-08-15
AI Technical Summary
The prior art lacks the impurity synthesis process of bifunctional active compounds of β2 adrenal receptor agonist and M receptor antagonist, which affects the quality, safety and effectiveness of the drug.
Impurities of bifunctional active compounds of β2 adrenal receptor agonist and M receptor antagonist were prepared by acetylation reaction and hydrogenation reaction. Acetylation reagents such as acetyl chloride and alkali promoters such as N,N-diisopropylethylamine were used for aminoacetylation, and then hydrogenation of debenzyl was performed through catalysts such as palladium catalysts and purification by liquid chromatography.
High-purity impurity compounds were successfully prepared as reference materials for the raw material JKN2304, and the quality control ability of drug research and development was improved.
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Abstract
Description
Technical Field
[0001] The present application belongs to the field of chemical pharmaceutical technology, and in particular relates to a method for preparing impurities of a bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist and its application. Background Art
[0002] Compounds with dual-functional active quaternary ammonium salt structures of β2 adrenergic receptor agonists and M receptor antagonists have the characteristics of few adverse reactions and low toxic side effects in the treatment of lung diseases such as COPD and asthma, and have broad application prospects.
[0003] However, for APIs such as JKN2304, which have a dual-functional active quaternary ammonium salt structure as a β2 adrenergic receptor agonist and an M receptor antagonist, the use of mixed anhydrides of formic acid and acetic anhydride as a formylation reagent during the aminoformylation process of the synthesis process inevitably produces acetylated products, which are the main impurities of API JKN2304. During the preparation research of JKN2304, impurities of API JKN2304 were discovered, and their structure is shown in Formula I.
[0004] JKN2304;
[0005] Formula I.
[0006] Substances that affect drug purity are collectively referred to as impurities. The study of impurities is an important part of drug research and development. It includes selecting appropriate analytical methods, accurately distinguishing and measuring the content of impurities, and determining reasonable limits for impurities based on the results of pharmaceutical, toxicological, and clinical studies. This study runs through the entire process of drug research and development. At the same time, the adverse reactions of drugs during clinical use are not only related to the pharmacological activity of the drugs themselves, but sometimes also have a great relationship with the impurities present in the drugs. Therefore, the treatment of impurities is related to the quality, safety, and efficacy of drugs. Currently, the treatment of impurities in the drug preparation process mainly includes separation and purification, monitoring and control, and research and evaluation, which require the use of reference substances. However, there is currently no literature reporting a method for synthesizing the impurities of the raw material drug JKN2304. Therefore, it is necessary to develop a method for synthesizing the impurities of a dual-functional active compound of β2 adrenergic receptor agonist and M receptor antagonist, that is, the impurities of the raw material drug JKN2304, and provide reference substances to meet the needs of drug research and development. Summary of the Invention
[0007] In view of this, the present application provides a method for preparing impurities of a bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist and its application, which is used to solve the technical problem of the lack of an impurity synthesis process for a bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist in the prior art.
[0008] In a first aspect, the present application provides a method for preparing an impurity of a bifunctional active compound of a β2 adrenergic receptor agonist and an M receptor antagonist, comprising the following steps:
[0009] Step S1, subjecting the compound represented by Formula II to an acetylation reaction of the amino group to obtain a compound represented by Formula III;
[0010] Step S2, subjecting the compound represented by Formula III to a hydrogenation reaction to debenzylation to obtain an impurity of the bifunctional active compound represented by Formula I as a β2 adrenergic receptor agonist and an M receptor antagonist;
[0011] Formula II;
[0012] Formula III;
[0013] Formula I.
[0014] Preferably, in step S1, the acetylation reagent used in the acetylation reaction is selected from at least one of acetyl chloride, acetic anhydride, and glacial acetic acid.
[0015] Preferably, in step S1, the base promoter used in the acetylation reaction is at least one selected from N,N-diisopropylethylamine, triethylamine, potassium carbonate, and sodium carbonate.
[0016] Preferably, in step S1, the molar ratio of the compound represented by formula II, the acetylating agent used in the acetylation reaction, and the base accelerator used in the acetylation reaction is: 1:1.1-2.0:3-5.
[0017] Preferably, in step S1, the acetylation reaction is carried out at a temperature of -10 to 50°C and for a time of 0.5 to 18 hours.
[0018] Preferably, in step S1, the organic solvent used in the acetylation reaction is selected from at least one of dichloromethane, chloroform, tetrahydrofuran, and N,N-dimethylformamide.
[0019] Preferably, in step S2, the catalyst used in the hydrogenation reaction is selected from at least one of a palladium catalyst, a platinum catalyst, a rhodium catalyst, and a ruthenium catalyst, and the hydrogen pressure is 0.2-0.5 MPa.
[0020] Preferably, in step S2, the hydrogenation reaction temperature is 5-50° C., and the time is 1-12 h.
[0021] Preferably, in step S2, the solvent used in the hydrogenation reaction is a mixed solvent of water and methanol in a volume ratio of 1 to 3:10.
[0022] Preferably, in step S1, after the acetylation reaction, a post-treatment step is further included: adding saturated saline to the product solution of the acetylation reaction for washing, removing the aqueous phase with a separatory funnel, drying the organic phase with anhydrous magnesium sulfate, filtering to remove the anhydrous magnesium sulfate, and concentrating under reduced pressure.
[0023] Preferably, saturated saline is added to the product solution of the acetylation reaction for washing, and the aqueous phase is removed by a separatory funnel, and the extraction is repeated 1 to 5 times.
[0024] Preferably, the solid compound of formula III or the concentrated solution of the compound of formula III is obtained by concentration under reduced pressure.
[0025] Preferably, in step S2, after the debenzylation reaction by hydrogenation, a post-treatment step is further included: filtering to remove the catalyst used in the hydrogenation reaction, and concentrating under reduced pressure to obtain a concentrated solution of the compound represented by formula I.
[0026] Preferably, after step S2, step S3 is further included;
[0027] Step S3 comprises: subjecting the concentrated solution of the compound represented by formula I to liquid chromatography purification, collecting the middle fraction of the main peak, and obtaining the purified compound represented by formula I.
[0028] Preferably, the chromatographic column used in the liquid chromatography purification process is kromasil 100-5-C18, the filler is C18 silica gel, the mobile phase A is acetonitrile, and the mobile phase B is 0.2% acetic acid aqueous solution.
[0029] Preferably, the elution mode of the liquid chromatography purification is gradient elution;
[0030] The parameters for gradient elution are:
[0031]
[0032] The second aspect of the present application provides the application of impurities of the bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist shown in Formula I in the field of drug research and development.
[0033] Compared with the prior art, the impurity preparation method and application of the bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist provided in this application include at least the following beneficial effects:
[0034] 1. In the preparation method provided in the present application, by using acetylation reagents such as acetyl chloride and base promoters such as N,N-diisopropylethylamine, the acetylation of the amino group was successfully achieved, and then debenzylation was performed by hydrogenation reaction to successfully prepare the impurities of the bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist shown in Formula I. The impurities of the bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist shown in Formula I can be used as a reference substance for the raw material drug shown in JKN2304 during the research and development process.
[0035] 2. In the preparation method provided in this application, a high-purity compound represented by Formula I is obtained by liquid chromatography purification, which can be used as a high-quality reference substance in the research and development process of the raw material drug represented by JKN2304. BRIEF DESCRIPTION OF THE DRAWINGS
[0036] In order to more clearly illustrate the specific implementation methods of the present application or the technical solutions in the prior art, the following is a brief introduction to the drawings required for use in the specific implementation methods or the description of the prior art. Obviously, the drawings described below are some implementation methods of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without any creative work.
[0037] Figure 1 This is the impurity nuclear magnetic resonance 1 H NMR spectrum of the bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist provided in Example 1 of the present application;
[0038] Figure 2 This is the impurity nuclear magnetic resonance 13C NMR spectrum of the bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist provided in Example 1 of the present application;
[0039] Figure 3 This is a high-resolution mass spectrum of impurities of the bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist provided in Example 1 of the present application;
[0040] Figure 4 This is the impurity HPLC spectrum of the bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist provided in Example 1 of the present application. DETAILED DESCRIPTION
[0041] The present application provides a method for preparing impurities of a bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist and its application, which is used to solve the technical problem of the lack of an impurity synthesis process for a bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist in the prior art.
[0042] The following will clearly and completely describe the technical solution of this application in conjunction with the accompanying drawings. Obviously, the embodiments described are only part of the embodiments of this application, not all of them. Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of this application.
[0043] Given that in the current aminoformylation process of the raw material drug having a bifunctional active quaternary ammonium salt structure of a β2 adrenergic receptor agonist and an M receptor antagonist as shown in JKN2304, a mixed anhydride of formic acid and acetic anhydride is used as a formylation reagent, which easily leads to the production of impurities of the bifunctional active compound of the β2 adrenergic receptor agonist and the M receptor antagonist as shown in Formula I. In order to meet the research and development requirements of the raw material drug having a bifunctional active quaternary ammonium salt structure of a β2 adrenergic receptor agonist and an M receptor antagonist as shown in JKN2304, it is necessary to provide the impurities of the bifunctional active compound of the β2 adrenergic receptor agonist and the M receptor antagonist as shown in Formula I as a reference substance; the present application provides a method for preparing impurities of the bifunctional active compound of the β2 adrenergic receptor agonist and the M receptor antagonist, the preparation method comprising: subjecting the compound shown in Formula II to an acetylation reaction of the amino group to obtain the compound shown in Formula III, and then subjecting the compound shown in Formula III to a hydrogenation reaction to debenzylation to obtain the impurities of the bifunctional active compound of the β2 adrenergic receptor agonist and the M receptor antagonist as shown in Formula I.
[0044] JKN2304;
[0045] Formula II;
[0046] Formula III;
[0047] Formula I.
[0048] Preferably, in the acetylation reaction, an acetylating agent and an alkaline promoter are required to activate reaction substrates such as the compound shown in Formula II and promote the acylation reaction. In the acetylation reaction step of the preparation method provided in the present application, the acetylating agent can use acetyl chloride, acetic anhydride, glacial acetic acid and other components, and the alkaline promoter can use N,N-diisopropylethylamine, triethylamine, potassium carbonate, sodium carbonate and other components. At the same time, in order to improve the selectivity of the reaction, acetylation is carried out at the amino group, and acetylation of groups such as hydroxyl groups is avoided as much as possible. In the present application, acetyl chloride should be used as the acetylating agent, and N,N-diisopropylethylamine should be used as the alkaline promoter.
[0049] Preferably, in the acetylation reaction, in order to promote the full reaction of reaction substrates such as the compound represented by formula II, the preparation method provided in the present application controls the dosage, reaction temperature and time in the acetylation reaction step; the molar ratio of the compound represented by formula II, the acetylating agent and the base promoter used in the acetylation reaction is 1:1.1~2.0:3~5, and the reaction temperature is -10~50°C and the reaction time is 0.5~18h.
[0050] Preferably, in the hydrogenation reaction, a catalyst and a hydrogen atmosphere are required to fully promote the debenzylation of the compound represented by Formula III by hydrogenation reaction; in the debenzylation step of the hydrogenation reaction in the preparation method provided in the present application, a palladium catalyst, a platinum catalyst, a rhodium catalyst, a ruthenium catalyst or the like can be used, and the hydrogen atmosphere pressure is 0.2~0.5MPa, and the reaction temperature of the hydrogenation reaction is controlled to be 5~50°C, and the time is 1~12h.
[0051] Preferably, the purity of the impurities of the bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist shown in Formula I will affect the quality of the reference substance for drug research and development; after the impurities of the bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist shown in Formula I are obtained by acetylation reaction and hydrogenation reaction, the present application further performs purification, and the purification is liquid chromatography purification; during the liquid chromatography purification process, the purity is further improved, and the present application collects the middle fraction of the main peak to obtain a highly purified compound shown in Formula I; the highly purified compound shown in Formula I can then be lyophilized and stored for future use.
[0052] Preferably, for the purpose of removing unreacted raw materials, catalysts and other components in the acetylation reaction and hydrogenation reaction, the present application also performs post-treatment on the compound of formula III obtained after the acetylation reaction and the compound of formula I obtained by the hydrogenation reaction; the post-treatment of the compound of formula III obtained after the acetylation reaction is to add saturated salt water to the product solution of the acetylation reaction for washing, remove the saturated aqueous phase with a separatory funnel and retain the organic phase, repeat three times, then add anhydrous magnesium sulfate to dry the organic phase, filter out the anhydrous magnesium sulfate, and concentrate under reduced pressure; the reduced pressure concentration can obtain a solid compound of formula III or a concentrated solution of the compound of formula III; when the compound of formula III is a solid, the yield of the acetylation reaction can be calculated; and the post-treatment of the compound of formula I obtained by the hydrogenation reaction is to filter out the catalyst and concentrate under reduced pressure to obtain a concentrated solution of the compound of formula I; the concentrated solution of the compound of formula I can be directly purified by liquid chromatography.
[0053] Correspondingly, the present application also provides the application of impurities of the bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist shown in Formula I in the field of drug research and development; considering that the purity of the compound of Formula I will affect the quality of the reference substance as a drug research and development, the present application uses the compound of Formula I purified by liquid chromatography for application in drug research and development.
[0054] The impurities of the bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist represented by Formula I provided in the present application will be described below with reference to the Examples and Experimental Examples.
[0055] Example 1
[0056] Example 1 of the present application provides a method for preparing impurities of a bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist shown in Formula I, the preparation method comprising the steps of acetylation of the amino group, debenzylation by hydrogenation, and purification by liquid chromatography.
[0057] The acetylation reaction of the amino group comprises the following steps: adding 6.0 g of the compound of formula II and 100 mL of dichloromethane to a reaction flask, stirring and dissolving, cooling to 0-5° C., adding 2.87 g of N,N-diisopropylethylamine (DIPEA), dropwise adding 0.65 g of acetyl chloride, and reacting at 5-10° C. for 9 hours; after the reaction is completed, washing with 50 mL of saturated brine and separating the aqueous phase with a separatory funnel, repeating the extraction three times, drying the extracted organic phase over anhydrous magnesium sulfate, filtering the anhydrous magnesium sulfate, and concentrating the filtrate under reduced pressure to obtain 6.8 g of a crude product of the compound represented by formula III.
[0058] The debenzylation step of the hydrogenation reaction comprises: adding the compound represented by Formula III to a hydrogenation kettle, adding 70 mL of methanol and 7 mL of water, and stirring to dissolve; adding 0.6 g of 10% Pd / C, replacing the atmosphere with nitrogen three times, replacing the atmosphere with hydrogen three times, passing hydrogen to about 0.5-2.0 MPa, stirring at 20-30° C. for 6 hours, and after completion of the reaction, filtering to remove Pd / C, and concentrating the filtrate under reduced pressure to obtain a crude compound represented by Formula I.
[0059] The liquid chromatography purification step comprises: purifying the crude compound represented by Formula I by liquid chromatography (Agilent 1260); the chromatographic column during the liquid chromatography purification process is kromasil 100-5-C18, the filler is C18 silica gel; the mobile phase A is acetonitrile; the mobile phase B is a 0.2% acetic acid aqueous solution, and the detection wavelength is 254 / 210 nm; gradient elution is performed according to the parameters shown in Table 1, and the middle portion of the main peak fraction is collected and lyophilized to obtain 2.5 g of a white solid, which is the purified solid compound represented by Formula I.
[0060] Table 1: Gradient elution parameters
[0061]
[0062] In this example, the chemical structures of the compound represented by Formula II, the compound represented by Formula III, and the compound represented by Formula I are shown below.
[0063] Formula II;
[0064] Formula III;
[0065] Formula I.
[0066] Experimental Example 1
[0067] In Experimental Example 1 of the present application, the impurities of the bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist represented by Formula I provided in Example 1 were detected by hydrogen and carbon spectra using a nuclear magnetic resonance device Burker AVANCE III AV 400, mass spectrometry using a mass spectrometer Agilent 1290 (UPLC-Q-TOF-MS), and chromatography using a liquid chromatograph Agilent 1260. The spectrum is shown as follows: Figure 1-4 shown.
[0068] from Figure 1-4 It can be seen that from Figure 1-4 The nuclear magnetic resonance 1H NMR spectrum, nuclear magnetic resonance 13C NMR spectrum, high-resolution mass spectrum and HPLC spectrum shown in the figure can qualitatively and quantitatively show that the present application has successfully synthesized the impurities of the bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist shown in Formula I, and the purity is relatively high. This shows that in the preparation method provided in Example 1 of the present application, the acetylation reaction of the amino group and the debenzylation reaction of the hydrogenation reaction are successfully carried out to obtain the compound shown in Formula I, thereby meeting the requirements of the reference substance in the research and development process of the raw material drug with a bifunctional active quaternary ammonium salt structure of β2 adrenergic receptor agonist and M receptor antagonist shown in JKN2304.
[0069] The specific process of chromatographic detection using liquid chromatography Agilent 1260 is as follows:
[0070] Accurately weigh the impurities of the bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist represented by Formula I and dissolve it in acetonitrile-phosphate solution (15:85) to prepare a solution containing 0.5 mg per 1 ml as the impurity reference solution.
[0071] Accurately measure 20 μl of the impurity reference solution, inject it into the liquid chromatograph, and record the chromatogram. If there are other impurity peaks in the chromatogram of the impurity reference solution, those with a retention time before 3 minutes will be disregarded, indicating that the solution contains the compound represented by Formula I, and calculate its content by the peak area normalization method;
[0072] Among them, the chromatographic conditions of liquid chromatography Agilent 1260 are:
[0073] Chromatographic column: kromasil 100-5-C18 column 4.6×250mm;
[0074] Column temperature: 30°C;
[0075] Mobile phase A: acetonitrile-phosphate solution (15:85). Prepare by dissolving 3.6 g of sodium dihydrogen phosphate dihydrate and 1.0 g of ammonium chloride in 1000 ml of water. Adjust the pH to 2.5 with phosphoric acid.
[0076] Mobile phase B: methanol-acetonitrile-phosphate solution (30:40:30). Prepare by dissolving 3.6 g of sodium dihydrogen phosphate dihydrate and 1.0 g of ammonium chloride in 1000 ml of water and adjusting the pH to 2.5 with phosphoric acid.
[0077] Flow rate: 1 mL / min;
[0078] Wavelength: 210nm.
[0079] The elution gradient is as follows:
[0080]
[0081] Taking the raw material drug JKN2304 as an example, the application of the impurities of the bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist represented by Formula I in the field of drug research and development refers to the specific process of chromatographic detection using the above-mentioned liquid chromatography Agilent 1260; the impurity reference solution of the compound represented by Formula I is replaced with the raw material drug JKN2304 solution, and based on the obtained chromatogram, the impurities of the bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist represented by Formula I in the raw material drug JKN2304 are calculated by the peak area normalization method, that is, based on the ratio of the chromatographic peak area of the component at a retention time of 42 minutes in the chromatographic peak to the sum of the peak areas of all components, the impurities of the bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist represented by Formula I in the raw material drug JKN2304 are calculated, thereby controlling the quality, safety and efficacy of the raw material drug JKN2304.
[0082] At the same time, in addition to the peak area normalization method for testing the impurities of the bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist shown in Formula I in the raw material JKN2304, the "impurities of the bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist shown in Formula I" provided in this application can also be used as an internal standard and added to the raw material JKN2304 solution for internal standard method testing; of course, it can also be configured as a set of standard solutions for external standard method testing.
[0083] The above embodiments are only used to illustrate the technical solutions of the present application, rather than to limit them. Although the present application has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present application.
Claims
1. A method for preparing an impurity of a bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist, characterized in that: The following steps are involved: Step S1, subjecting the compound represented by Formula II to an acetylation reaction of the amino group to obtain a compound represented by Formula III; Step S2, subjecting the compound represented by Formula III to a hydrogenation reaction for debenzylation to obtain an impurity of a bifunctional active compound represented by Formula I that is a β2 adrenergic receptor agonist and an M receptor antagonist; Formula II; Formula III; Formula I.
2. The method for preparing an impurity of a β2 adrenergic receptor agonist and M receptor antagonist dual-functional active compound according to claim 1, characterized in that: In step S1, the acetylation reagent used in the acetylation reaction is at least one selected from acetyl chloride, acetic anhydride, and glacial acetic acid.
3. The method for preparing an impurity of a β2 adrenergic receptor agonist and M receptor antagonist dual-functional active compound according to claim 1, characterized in that: In step S1, the base promoter used in the acetylation reaction is at least one selected from N,N-diisopropylethylamine, triethylamine, potassium carbonate, and sodium carbonate.
4. The method for preparing an impurity of a β2 adrenergic receptor agonist and M receptor antagonist dual-functional active compound according to claim 1, characterized in that: In step S1, the molar ratio of the compound represented by formula II, the acetylating agent used in the acetylation reaction, and the base accelerator used in the acetylation reaction is: 1:1.1-2.0:3-5.
5. The method for preparing an impurity of a β2 adrenergic receptor agonist and M receptor antagonist dual-functional active compound according to claim 1, characterized in that: The acetylation reaction temperature is -10 to 50° C., and the reaction time is 0.5 to 18 hours.
6. The method for preparing an impurity of a β2 adrenergic receptor agonist and M receptor antagonist dual-functional active compound according to claim 1, characterized in that: In step S2, the catalyst used in the hydrogenation reaction is selected from at least one of a palladium catalyst, a platinum catalyst, a rhodium catalyst, and a ruthenium catalyst, and the hydrogen pressure is 0.2-0.5 MPa.
7. The method for preparing an impurity of a β2 adrenergic receptor agonist and M receptor antagonist dual-functional active compound according to claim 1, characterized in that: In step S2, the hydrogenation reaction temperature is 5-50° C. and the time is 1-12 h.
8. The method for preparing an impurity of a β2 adrenergic receptor agonist and M receptor antagonist dual-functional active compound according to claim 1, characterized in that: After step S2, the method further includes step S3; Step S3 comprises: subjecting the solution of the compound represented by formula I to liquid chromatography purification, collecting the middle fraction of the main peak, and obtaining the purified compound represented by formula I.
9. The method for preparing an impurity of a β2 adrenergic receptor agonist and M receptor antagonist dual-functional active compound according to claim 8, characterized in that: The chromatographic column filler used in the liquid chromatography purification process is C18 silica gel, the mobile phase A is acetonitrile, and the mobile phase B is 0.2% acetic acid aqueous solution.
10. Use of impurities in the bifunctional active compound of β2 adrenergic receptor agonist and M receptor antagonist prepared by the preparation method according to claims 8-9 in the field of pharmaceutical research and development.
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